2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole, also known as lansoprazole, is disclosed in Japanese patent application No. JP-A-61-50978.
Lansoprazole is a well-known gastric acid secretion inhibitor and is useful as an anti-ulcer agent. Lansoprazole has a chiral sulfur within its molecular structure and, hence, occurs as two optical isomers, R-lansoprazole and S-lansoprazole.
U.S. Pat. No. 6,462,058 B1 discloses a crystal of R-lansoprazole and its use as an anti-ulcer agent. U.S. Pat. Nos. 6,462,058 B1 and 6,664,276 B2 and PCT Patent Publication No. WO 00/78745 A2 all describe methods to obtain crystals of R-lansoprazole. Exemplary methods for such synthesis include:
a) A fractional crystallization method in which a salt between a racemate lansoprazole mixture and an optically active compound [for example, (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid, or (−)-tartaric acid] is formed. The resulting salt is separated by fractional crystallization and then subjected to a neutralization process to give a free optical isomer.
b) A chiral column method in which a racemate or a salt is applied to a column for optical isomer separation. In liquid chromatography, for example, optical isomers are separated by adding the racemate to a chiral column (such as the Daicel® series, produced by Daicel Chemical Industries, Ltd.), and eluting in water, a buffer (for example, a phosphate), an organic solvent (for example, hexane, ethanol, methanol, isopropanol, acetonitrile, triethylamine, or mixtures thereof) or mixtures of the foregoing.
c) A diastereomer method in which a racemate and an optically active reagent are reacted to give a diastereomer mixture. The diastereomer mixture is separated to obtain the desired diastereomer, and the optically active reagent is cleaved.
U.S. Pat. Nos. 6,462,058 B1 and 6,664,276 B2 and PCT Patent Publication No. WO 00/78745 A2 also describe the synthesis of various polymorphic forms of R-(+)-lansoprazole. Some of the polymorphic forms described in these references include: a) an amorphous form that is relatively unstable; b) a crystalline anhydrous form; and c) a crystalline sesquihydrate form. These references further provide X-ray powder diffraction characteristics of the crystalline forms of R-(+)-lansoprazole and the use of the crystalline R-(+)-lansoprazole for manufacturing a pharmaceutical composition for the treatment or prevention of a digestive ulcer.
U.S. Pat. Nos. 6,462,058 B1 and 6,664,276 B2 and PCT Patent Publication No. WO 00/78745 A2 also suggest that various salts of R-(+)-lansoprazole may be prepared such as metal salts, salts of organic bases and salts with amino acids. These references fail to provide any examples for preparing such salts.
U.S. Published Patent Application No. 2003/0181487 A1 describes various metal salts of R-(+)-lansoprazole, including the sodium salt, magnesium salt, lithium salt, calcium salt and barium salt as well as processes for manufacturing these metal salts. This published application states that these metal salts could be used in solid form and exhibited good stability characteristics.
Different salt forms of a pharmaceutically active compound can exhibit different bioavailabilty, solubility, color, compressibility, flowability and/or stability with consequent modification of the profiles of toxicological, safety, clinical effectiveness and productive efficiency. Improved drug formulations are consistently sought after for better bioavailability, better processing characteristics and/or better stability. There is also an ongoing need for new or purer forms of existing drug molecules.